Controlled release oral dosage form

ABSTRACT

A once a day bupropion hydrochloride formulation is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims is a continuation-in-part of the convertednonprovisional application (Ser. No. not yet assigned) of U.S.Provisional Application Ser. No. 60/267,457, filed Feb. 8, 2001 and theconverted nonprovisional application (Ser. No. not yet assigned). ofU.S. Provisional Application Ser. No. 60/267,456, filed Feb. 8, 2001,which converted nonprovisional applications are in turn acontinuation-in-part of U.S. Pat. No. 6,210,716.

FIELD OF THE INVENTION

The present invention relates to oral controlled release dosageformulations containing bupropion hydrochloride.

BACKGROUND OF THE INVENTION

The compound designated bupropion hydrochloride is described in U.S.Pat. Nos. 3,819,706 and 3,885,046. It is marketed as an anti-depressantand an aid to smoking cessation. Bupropion is an aminoketone-derivativechemically unrelated to other currently available antidepressants (e.g.,selective serotonin-reuptake inhibitors, tricyclics, tetracyclics).

While the neurochemical mechanisms of the antidepressant and smokingcessation effects are unknown, noradrenergic pathways and/ordopaminergic effects appear to be primarily involved. Bupropion does notinhibit monoamine oxidase and is a weak blocker of serotonin andnorepinephrine uptake.

The drug is useful in the treatment of depressive affective disorders(e.g., major depression) at dosages of 75 to 600 mg daily. Bupropion maybe preferable to other agents because of its minimal anticholinergic,cardiovascular, and antihistaminic effects or in those patients who haveexperienced weight gain or sexual dysfunction with anotherantidepressant. Bupropion, as extended-release tablets, is used in thecessation of smoking at dosages of 100-300 mg daily. Withdrawal symptomsand cigarette craving are reduced with bupropion. Other uses includepatients with bipolar depression, attention-deficit hyperactivity inboth adult and pediatric patients, and panic symptoms superimposed ondepression.

Immediate release bupropion tablets provide more than 75% of bupropionrelease into the dissolution media in 45 minutes. In studies to date,the risk of seizures appears to be strongly associated, in part, withthe use of instant release tablets.

Numerous techniques exist in the prior art for preparing sustained orcontrolled release pharmaceutical formulations. One common techniqueinvolves surrounding an osmotically active drug core with asemipermeable membrane. The drug is released from the core over time byallowing a fluid such as gastric or intestinal fluid to permeate thecoating membrane and dissolve the drug so the dissolved drug canpermeate through the membrane. In some cases a hydrogel is employed topush the active ingredient through the passageway of the membrane.

Another common technique for preparing controlled-release pharmaceuticalformulations is to encapsulate a plurality of beads, pellets or tabletsthat are coated with varying levels of diffusion barriers. The barrierscan be of the same or different chemical composition: Release of thepharmaceutical may occur by leaching, erosion, rupture, diffusion orsimilar actions depending on the nature and thickness of the coatingmaterial. These products require multi-layered coating, sometimes asmuch as 30 to 90 coats.

Film coating techniques are characterized by the deposition of a uniformfilms onto the surface of a substrate. Because of the capability ofdepositing a variety of coating materials onto solid cores, this processhas been used to make controlled release dosage forms starting fromdifferent formulations, such as tablets, granules, pellets and capsules.Cores are usually prepared using one of the following processes:compaction, surface layering, or agglomeration.

One limitation associated with these dosage forms consists in theirfailure to delay drug delivery. Many of the multi-walled preparationsdescribed above do not provide prolonged delayed release of the drug-prior to initiation of sustained release, which is important whenbiphasic release profiles are desired. Other systems are essentially“delayed” releases mechanisms. There is delay of drug release in thestomach, but once the coated drug reaches the intestines, the release ofmedication is rapid. There is no sustained release in the intestines.

Bupropion hydrochloride is highly soluble in water with a highpermeability characterized by rapid and almost complete absorption. Peakplasma concentrations occur within 2 hours for bupropion and 3 hours forbupropion sustained-release. Its biphasic pharmacokinetics ischaracterized by a two-compartment model; the distributive phase has amean half-life of 3 to 4 hours with a biphasic decline and a terminal T½ of about 14 hours following single doses. A major drawback isextensive first-pass metabolism. It appears that only a small portion ofany oral dosage reaches the systemic circulation intact.Immediate-release tablets are dosed three times a day, preferably with 6or more hours separating the doses. For those patients requiring dosesgreater than 300 mg daily, each divided dose should not exceed 150 mgeach. This necessitates administration of the tablets 4 times daily withat least 4 hours between. successive doses. Commercially availablesustained-release products are available in film-coated tablets marketedby Glaxo Wellcome under the tradenames Wellbutrin® SR and Zyban®. Theseare dosed twice daily. For those patients requiring above 300 mg daily,the regimen remains twice daily dosing. No currently available productprovides a sustained release profile suitable for once daily dosing.

Patient compliance is especially problematic in depressed patients.There is a need for improved patient compliance. One of the meansemployed clinically to improve patient adherence to therapy issimplification of the dosing regimen. Thus, need exists for a once dailybupropion formulation.

Sustained release tablet forms of bupropion are described in U.S. Pat.No. 5,427,798, comprising a sustained release tablet which provides peakbupropion blood levels at approximately 2-3 hours, thereby requiringtwice daily dosing. Controlled release is achieved by combiningbupropion particles with microcrystalline cellulose and hydrogel-forminghydroxypropyl methylcellulose.

Another sustained release bupropion tablet or caplet formulationdisclosed in U.S. Pat. No. 4,687,660, comprises a difficultmanufacturing process and limited shelf life. U.S. Pat. No. 5,358,970discloses a formulation of bupropion hydrochloride that contains an acidstabilizer.

U.S. Reissue Pat. No. 33,994 discloses a tablet formulation of a waterinsoluble, water-permeable film coating surrounding the drug core and aparticulate, water-soluble, pore-forming material dispersed within thefilm coating; this osmotic gradient and channel forming system isapplicable for tablet dosage forms. However, here also at least twicedaily dosing is necessitated by the release profile of 25-70% ofbupropion within 4 hours, and 40-90% within 6 hours. Wellbutrin® SR is acommercially available twice a day dosage form of bupropion whichcontains carnauba wax, cysteine hydrochloride, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose,polyethylene glycol and titanium dioxide.

There is no capsule form of bupropion commercially available. Capsulesare advantageous in those patients who have difficulty swallowing wherethe contents of the capsule may be sprinkled on food.

Immediate release tablets must be stored at a temperature above 15-25°C. and protected from light and moisture. Extended-release tabletsshould be stored in tight, light-resistant containers at a temperatureof 20-25° C.

The need exists for a delayed, sustained release pharmaceuticalpreparation that provides a longer delay of drug dissolution therebyallowing greater flexibility in designing sustained release profiles,provides improved plasma levels wherein the maximum plasma concentration(C_(max)) can be substantially reduced without a concomitant reductionin AUC, and is simply and economically produced. Such a delayed deliverydosage form has a practical application, and it represents a valuablecontribution to the medical arts. The present invention provides such acomposition, and offers an efficient and cost effective method ofpreparation.

Accordingly, it is an object of this invention to provide a sustainedrelease formulation of bupropion suitable for once daily administration.

Another object of the present invention is to provide a capsule dosageform comprising means for delaying delivery of the drug in gastricfluids for 6 hours up to 12 hours, usually 4 hours to 8 hours.

It is also an object of this invention to provide a controlled andextended release bupropion capsule formulation that is easy tomanufacture and can be used to prepare a range of dosing levels suitablefor once daily administration.

It is a further object of the present invention to provide 24-hourcontrol of symptoms of depression or tobacco dependence withdrawal.

Seizures result more commonly by single dosages of bupropion over 150mg, hence the need for twice to four times daily dosing regimens.Another object of this invention is to provide simplified once dailydosing regimen with the potential to prevent or reduce the incidence ofseizures caused by bupropion.

The present invention also relates to a new sustained release bupropionpharmaceutical composition producing novel blood plasma levels afteringestion over 24 hours that is not disclosed in, nor rendered obviousby, the prior art. Other objects, features and advantages of theinvention are not taught in the prior art but will be more apparent tothose versed in the art from the following specification, taken inconjunction with the drawings.

SUMMARY OF THE PRESENT INVENTION

The present invention meets the unfulfilled needs of the pharmaceuticalindustry.

The current invention involves a new pelletization process, typified bythe application of a bupropion/cellulose ether suspension to inertspheres and two unique formulations of sustained release coatings thatare applied to separate active pellets. The formulation functions bymembrane-controlled extended-release in a pH dependent manner. Thebupropion release rate has been improved by the introduction of twotypes of film coated active pellets that release the drug at differentpH resulting in novel dissolution profiles.

Inert spheres are initially coated with bupropion and hydroxypropylmethylcellulose. The active pellets containing bupropion comprise 70-75weight % of the dosage form. An enteric coating, applied to about onethird of the active drug pellets, is comprised of a film insoluble atlow pH, such as hydroxypropyl methylcellulose phthalate. The secondcoating applied to the other two thirds of active drug pellets iscomprised of a combination of a hydrophobic coating agent and methylacrylic acid copolymer. The two pellet types are then combined in acapsule. Generally, the weight ratio of the first pellet to the secondpellet will be from about 90:10 to about 10:90, although a weight ratioof from about 30:70 to about 70:30 is preferred. Especially preferred isa weight ratio of about 33.3:66.7.

This formulation can provide 24-hour efficacy with once daily dosing,with less than 50% of the drug released at 10 hours. Therapeutic plasmalevels are maintained from 12 to 24 hours. The usual dosage range is75-450 mg.

In another embodiment of the present, an uncoated bupropion component isalso employed. In this embodiment, bupropion powder or granules, or theuncoated active pellets (bupropion and hydroxypropyl methylcellulosesprayed onto an inert sphere) may be used directly (first component).The bupropion release rate is further modified and improved by theintroduction of uncoated bupropion and the two types of film coatedactive pellets that release the drug at different pH resulting infurther novel dissolution profiles.

In this embodiment, the enteric coating (hydroxypropyl methylcellulosephthalate) is applied to from about 10 to about 90 weight percent of theactive drug pellets (second component). The second coating (hydrophobicand methyl acrylic acid copolymer) is applied to from about 90 to about10 weight percent of active drug pellets (third component). The threecomponents are then combined in a capsule. Generally, the weight ratioof the first component to the second component may vary from about 1:50to about 50:1 , the weight ratio of the first component to the thirdcomponent may vary from about 1:50 to about 50:1, and the weight ratioof the second component to the third component may vary from about 10:90to about 90:10, although a weight ratio of from about 30:70 to about70:30 is preferred. Especially preferred is a weight ratio of threecomponents of about 10:30:60.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the dissolution profile in a pH 7.5 bufferof the formulations as described in Examples 1 and 3 versus thedissolution of the commercially available sustained release form ofbupropion (Wellbutrin® SR).

FIG. 2 is a graph depicting the dissolution profile in simulated gastricfluid (pH 1.5) of the formulations as described in Examples 1 and 3versus the dissolution of the commercially available sustained releaseform of bupropion (Wellbutrin® SR).

FIG. 3 is a graph depicting the mean plasma concentration-time profilesof bupropion in seven healthy subjects (smokers) following a single oraldose of the formulation in Example 2 versus 150 mg of the commerciallyavailable sustained release product (Zyban®).

FIG. 4 is a graph depicting the mean plasma concentration-time profilesof bupropion in seven healthy subjects (smokers) following a single oraldose of the formulation in Example 4 versus 150 mg of the commerciallyavailable sustained release product (Zyban®).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention, in a first embodiment provides a two componentcontrolled release bupropion formulation for oral administration, theformulation comprising:

-   -   (1) a first pellet comprising:        -   (i) a core comprising:            -   (a) bupropion and its salts, isomers, or a                pharmaceutically acceptable aminoketone antidepressant                agent;            -   (b) an inert pellet as a starting material; and            -   (c) a binder; and;        -   (ii) a coating comprising:            -   (a) a pH dependent coating agent;            -   (b) a plasticizer; and            -   (c) a lubricant; and    -   (2) a second pellet comprising:        -   (i) a core comprising:            -   (a) bupropion and its salts, isomers, or a                pharmaceutically acceptable aminoketone antidepressant                agent;            -   (b) an inert pellet as a starting material; and            -   (c) a binder; and        -   (ii) a coating comprising:            -   (a) a methyl acrylic acid copolymer;            -   (b) a water insoluble polymer;            -   (c) a plasticizer; and            -   (d) an antisticking agent.

In other embodiments of the present invention, there may also be presentanother component, a form of immediate release bupropion.

The immediate release bupropion component may comprise any form ofimmediate release bupropion. This may take the form of uncoatedbupropion granules or powders, may comprise bupropion active pellets (asdescribed hereinbelow), may include bupropion granules or active pelletscoated with a highly soluble immediate release coating, such as anOpadry® type coating, as are known to those skilled in the art (seegenerally, U.S. Pat. No. 5,098,715), or a combination of any of theforegoing.

The active pellets of bupropion hydrochloride useful in the practice ofthe present invention are preferably based on active pellets having acore forming inert component that may comprise any type of commonlyknown pellet starting material, which may be water insoluble, such as,but not limited to, cellulose spheres or silicon dioxide, or may bewater soluble, such as, but not limited to, starch or sugar sphereshaving a diameter ranging from about 15 to about 50 mesh, preferablyranging from about 30 to about 35 mesh. The preferred pellet startingmaterial is sugar spheres, NF, containing not less than about 62.5percent and not more than about 91.5 percent of sucrose. The spheresshould have consistent bulk density, low friability, and low dustgeneration properties.

The inert core is preferably coated with an aminoketone antidepressantagent or a pharmaceutically acceptable salt or stereoisomer thereof Mostpreferably, the core drug is bupropion hydrochloride.

The core forming inert component is coated with a formulation thatcomprises bupropion hydrochloride and a binding agent. The binding agentshould be water soluble, and should possess high adhesivity and anappropriate viscosity, to guarantee good adhesion between the sugarcores and bupropion particles, resulting in a high concentration of drugin the pellets. The binding agents employed can be any type of bindingagent commonly known in the art such as polyvinyl pyrrolidone,hydroxyethyl cellulose, hydroxypropyl cellulose, low molecular weighthydroxypropyl methylcellulose (HPMC), polymethacrylate or ethylcellulose. In a preferred embodiment of the present invention, thebinding agent is a water-soluble polymer such as hydroxypropylmethylcellulose having a viscosity in the range of 2-12 cps at 20° C.,preferably 4-6 cps, such as the material sold as Methocel® E5. Apreferred composition of the binder for bupropion is about 2-10% w/w,and most preferably 3-5%.

The active pellets of the present invention will preferably comprise thefollowing ingredients: INGREDIENT PREFERRED MOST PREFERRED Bupropion HCl40-80% 60-70% HPMC  2-10% 2.5-5%   starting pellets 10-35% 15-30%All the percentages in the above-table are based on the total weight ofthe core.

The active pellets for use in the practice of the present invention thatcomprise the bupropion are typically prepared by forming a suspension ofthe binder and the drug and then layering the suspension onto thestarting pellet using any of the layering techniques known in theindustry, such as fluidized bed coating, rotor granulation or pancoating. The suspension medium may comprise any low viscosity solvent,such as isopropyl alcohol, ethanol, water, mixtures thereof and thelike. A sufficient amount of coating is applied to provide the desiredlevel of bupropion. These active pellets may be used directly as thefirst component of the three component formulations of the presentinvention.

The active pellets are also useful in preparing the other two componentsof the present invention (both the two component and three componentformulations). The active pellets intended for such use are divided intotwo groups, each group receiving a film coating that releases the drugat a different pH. One group of pellets is coated to release drug at apH corresponding to about 4.8 and lower, which is likely to occur in thetipper gastrointestinal (GI) tract; the other group of pellets is filmcoated to release drug at a pH of 7 and above, which is likely to occurin the lower GI tract. Thus, the entire does is released from thisproduct for an extended period of time during its transition through theGI tract.

In a preferred embodiment, one group of pellets (enteric component) iscoated with a film comprising a pH dependent coating polymer, aplasticizer and a lubricant. This group of pellets preferably comprisesfrom about 10 to about 90 weight percent of the total pellets,preferably from about 30 to about 70 weight percent, and most preferablyfrom about 33 to about 60 weight percent.

The pH dependent coating polymer may be selected from those entericcoatings known to those skilled in the art. Preferably, the pHdeperident coating is selected from the group consisting of shellac,methacrylic acid copolymers (such as, but not limited to Eudragit® E100(a cationic copolymer of dimethyl aminoethyl methacrylate and neutralmethacrylic acid esters)), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate trimellitate, polyvinyl acetate phthalateor mixtures thereof Hydroxypropyl methylcellulose phthalate (HPMCP) ispreferred. The preferred concentration is 2-10% w/w of the total dosageform, and most preferably 3-5%.

The coating preferably also contains plasticizers. Plasticizers that maybe used in the practice of the present invention include any of thoseknown to those skilled in the art, including, but not limited to,acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil,olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate,triethyl citrate, tributyl citrate, glyceroltributyrate, polyethyleneglycol, propylene glycol and mixtures thereof. The preferred plasticizeris acetyltributyl citrate in an amount ranging from about 1 to about 15percent based on the total weight of the final coating or 0.1-3% w/w ofthe total dosage form.

The coating further preferably includes a lubricant such as, but notlimited to, those selected from the group consisting of glycerylmonostearate; Myvaplex 600P, calcium stearate or stearic acid. Thepreferred lubricant is glyceryl monostearate in an amount ranging fromabout 1 to about 15 percent, and most preferably 1-2.5% based on thetotal weight of the coating.

A preferred enteric coating for use in the present invention thereforecomprises the following ingredients: INGREDIENT PREFERRED MOST PREFERREDHPMCP  2-10% 3-5% Acetyltributyl citrate 0.1-3%   0.5-1%   Glycerylmonostearate 1-3%   1-2.5%

Additional active drug pellets for forming the second coated componentof the present invention, preferably from about 90 to about 10 weightpercent of the total pellets, more preferably from about 70 to about 30weight percent, and most preferably from about 67 to about 40 weightpercent, are coated with a coating that comprises a polymer such as amethacrylic copolymer, water insoluble polymer, a plasticizer and ananti-sticking agent.

The methacrylic acid copolymer is selected from the known group ofmethacrylic acid copolymers, preferably Eudragit® S (methacrylic acidcopolymer Type B), and most preferably Eudragit® S100. The preferredconcentration is 1-15% of the total weight of the dosage form,preferably 4-7%.

The water insoluble polymer in the preferred embodiments of the presentinvention is formed from a cellulose ester, or a cellulose ester-ether.Representative materials include a member selected from the groupconsisting of ethyl cellulose, cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate butyrate, mono-, di- and tri-cellulosearylates, and the like. Preferred is ethyl cellulose in a concentrationranging from about 1 to about 20%, preferably from about 2 to about 13%.

The preferred plasticizer additive for the second coating may beselected from any of those mentioned above. Acetyltributyl citrate ispreferred.

The anti-sticking agents can be chosen from any of the known agents,such as, but not limited to, those selected from the group consisting ofan alkaline earth metal stearate, such as magnesium stearate or calciumstearate, or talc. The anti-sticking agents can be used alone or incombination in effective amounts. The preferred anti-sticking agent istalc.

The coating for the active pellet for this (second coated) component ofthe present invention is applied to the active pellets by forming asolution of the respective coating components in a solvent or a mixtureof solvents, such as, but not limited to, acetone and isopropyl alcohol,and employing any of the application techniques known to those skilledin the art, such as fluidized bed coating, rotor granulation or pancoating.

The components, either the two coated or the two coated and theimmediate release, of the present invention are blended together in thedesired ratio and placed in gelatin capsule to obtain a finishedproduct. By varying the ratio of the three components, including used ofthe immediate release at 0%, novel dissolution profiles and plasmaprofiles may be obtained in accordance with the present invention.Alternatively, the dosage formulation may be made into tablets by firstadding from 25 to 40 weight percent of a solid pharmaceuticallyacceptable tablet excipient that will form a compressible mixturewithout crushing the pellets, and then tabletting the mixture in asuitable tablet press.

The following examples are intended to illustrate the present inventionbut are not intended to limit the scope of the appended claims.

EXAMPLE 1

A batch of controlled release bupropion was manufacture using allmaterials that comply with the current USP/NF compendia specifications.

A controlled release 150 mg oral bupropion dosage form is prepared byforming active core pellets having the following composition: I. ACTIVECORE PELLETS Bupropion HCl 70.0% Sugar sphere 30/35 26.5% Methocel E53.5%

Active pellets of bupropion are formed by dissolving 2.8 kg of bupropionHCl and 0.140 kg of hydroxypropyl methylcellulose (Methocel® E5) in amixture of water and isopropyl alcohol. The active drug solution is thensprayed onto 1.06 kg of sugar spheres 30/35 in a fluidized bed processorwith a Wurster insert. The active core pellets are then dried in afluidized bed processor until the loss on drying is below 1%. Thebupropion pellets are then passed through a 16 mesh screen and a 30 meshscreen and pellets are collected that are smaller than 16 mesh andlarger than 30 mesh. II. ENTERIC COATED PELLETS Bupropion active pellets75.0% HPMCP 50 16.9% Acetyltributyl citrate 2.5% Myvaplex 600P 5.6%

For a group of about one-third of the pellets, 0.270 kg of hydroxypropylmethylcellulose phthalate and 0.040 kg of acetyltributyl citrate aredissolved in a mixture of purified water and isopropyl alcohol, USP.Then 0.090 kg of glyceryl monostearate (Myvaplex 600P) is dissolved intothe solution above. The solution is then sprayed onto 1.2 kg of thebupropion core pellets in a fluidized bed processor with a Wursterinsert. The pellets are then dried until the loss on drying (LOD) isless than 1%. The pellets are then mixed with 2% (w/w) talk for 10minutes in a V-blender. The pellets are then passed through a 14 meshscreen and a 24 mesh screen and pellets that are smaller than 14 meshand larger than 24 mesh are collected. III. SUSTAINED RELEASE (SR)COATED ACTIVE PELLETS Bupropion active pellets 80.0% Eudragit ® S10012.6% Ethocel ® 10 cps 1.4% Acetyltributyl citrate 2.0% Talc 4.0%

For another group of about two-thirds of the pellets, a coating isprepared where the ratio of the methacrylic acid copolymer toethylcellulose is about 9:1. The coating is made as follows: 0.378 kg ofmethacrylic acid copolymer (Eudragit® S 100), 0.42 kg of ethylcellulose(Ethocel® 10 cps), and 0.060 kg of acetyltributyl citrate are dissolvedin a mixture of 0.690 kg acetone and 6.210 kg isopropyl alcohol. 0.120kg of talc is then dispersed into the solution above. The suspension isthen sprayed onto 2.40 kg of the active bupropion core pellets in afluidized bed processor with a Wuster insert. The bupropion pellets aredried in a fluidized bed processor until the LOD is less than 1%. Thepellets are mixed with 2% (w/w) talc for 10 minutes in a V-blender andpassed through a 14 mesh screen and 24 mesh screen. Pellets smaller than14 mesh and larger than 24 mesh are collected.

These pellets have the following coating composition: INGREDIENTMG/CAPSULE % TOTAL WEIGHT Eudragit ® S100 22.5 6.4 Ethocel ® 10 cps 2.50.7 Acetyltributyl citrate 3.6 1.0 Talc 7.1 2.0

The enteric coated pellets and the SR pellets are mixed after loadingeach group into dosators. The strength of the final product is 150 mg ofbupropion with 50 mg of active drug in the first group of pellets and100 mg of active in the second group. The pellets are then encapsulatedinto size “1” light turquoise blue/light turquoise blue capsules. Thetotal weight of the formulation (capsule+pellets) is 350 mg.

The resulting bupropion capsules of Example 1 were then tested accordingto the USP XXIII dissolution test (type 2, basket) at 50 rpm, at 37° C.in pH 7.5 buffer and found to have the following release profile: TABLE1 Time (hours) % Released 1 25 2 60 3 75 4 80 6 88 8 93 10 93 12 94 1494 16 94

The release profile of the controlled release product shown in thisExample is shown in FIG. 1 by the line filled with circles.

The bupropion capsules of Example 1 were then tested according to theUSP XXIII dissolution test (type 2, basket), at 50 rpm, at 37° C. in SGF(pH 1.5) to determine the percentage of drug dissolved versus time.TABLE 2 Time (hours) % Released 1 0 2 1 3 2 4 3 6 7 8 15 10 30 12 45 1450 16 56 20 60

The release profile of the controlled release product shown in thisExample 1 is shown in FIG. 2 by the line with the filled circles.

The bopropion capsules of Example 1 were then evaluated in sevenpatients using standard techniques known in the art. Bupropion was firstdetected in the plasma at about 2 hours after administration, and showedsustained release over 24 hours.

Two panels of seven patients were randomly assigned to receive eitherthe bupropion formulation described herein or ZYBAN® in an open,randomized single dose study. Blood samples were collected over a72-hour period and analyzed for bupropion concentrations with a LC/MS/MSmethod.

For the blood levels carried out C_(max) is the maximum blood levelconcentration of bupropion, T_(max) is the time at which the maximumblood level concentration occurs, T_(lag) is the sampling pointpreceding the one at which concentrations first become quantifiable. AUCis the “area under the curve” of time versus blood concentration. Theresults provided are given in Table 3 and FIG. 3 show that the meanplasma concentration-time profiles of bupropion were different for theExample 1 formulation and Zyban®. Following oral administration, theExample 1 formulation had a delayed absorption with a T_(lag) value of1.9 hours. The mean C_(max) value of the Example 1 bupropion formulationwas about one-half of that for Zyban®. The time to reach (T_(max))maximum plasma concentration occurred about 8 hours after administrationof the Example 1 formulation. The relative bioavailability of theExample 1 formulation to Zyban® was 40% in terms of C_(max) and 80% interms of AUC_(0-inf) ratio. TABLE 3 Variable Example 1 Mean Zyban MeanG-Mean Ratio C_(max) (ng/ml) 54.2 129.0 0.40 AUC_(0-inf) (ng · hr/ml)832.0 998.0 0.80 T_(lag) (hr) 1.9 0.1 T_(max) (hr) 8.1 3.6 T_(1/2) (hr)17.0 20.3

Thus, it can be seen from the data above that although the C_(max) ofExample 1 is significantly lower than the C_(max) of the Zyban®formulation, the AUC has only been slightly reduced.

EXAMPLE 2

The pellets from Example 1 are taken as the second and third components.These pellets are loaded into the dosator along with active pellets andare filled into capsules in a ratio of 10:30:60 while maintaining thedosage at 150 mg. The blood profiles from this example will show aC_(max) that is the same as shown in Table 3, but will show a slightlyincrease AUC, thereby rendering the G-Mean ratio at about 1.00. Theamount of active pellets may be adjusted as is known in the art withoutundue experimentation based on the teachings of the present disclosurein order to substantially provide a G-Mean for AUC of approximately1.00.

EXAMPLE 3

The procedure of the Example 1 is followed for the first group ofpellets. The bupropion cores are prepared by forming a suspension ofbupropion and hydroxypropyl methylcellulose in a mixture of water andisopropyl alcohol, which suspension is spray coated onto inert spheres.The HPMCP enteric coating is then applied to about one third of theactive drug pellets.

Film Coating For SR Pellets

A second group of about two-thirds of the pellets is coated with acoating prepared where the ratio of methacrylic acid copolymer toethylcellulose is about 1:1. The pellets have the following composition:Bupropion active pellets 80.0% Eudragit ® S100 7.0% Ethocel ® 10 cps7.0% Acetyltributyl citrate 2.0% Talc 4.0%

The coating is made as follows: 0.105 kg of methacrylic acid copolymer(Eudragit® S100), 0.105 kg of ethylcellulose (Ethocel® 10 cps), and0.030 kg of acetyltributyl citrate are dissolved in a mixture of 0.345kg acetone and 3.105 kg isopropyl alcohol. 0.060 kg of talc is thendispersed into the solution above. The suspension formed is then sprayedonto 1.20 kg of the active bupropion core pellets in a fluidized bedprocessor with a Wurster insert. The coated bupropion pellets are thendried in a fluidized bed processor until the LOD is less than 1%. Thepellets are mixed with 2% (w/w) talc 10 minutes in a V-blender andpassed through a 14 mesh screen and a 24 mesh screen. Pellets smallerthan 14 mesh and larger than 24 mesh are collected.

The pellets have the following coating composition: Ingredientmg/Capsule % Total Wt. Methacrylic acid copolymer 12.5 3.6 Ethocel ® 10cps 12.5 3.6 Acetyltributyl citrate 3.6 1.0 Talc 7.1 2.0

The first group of pellets and the 1:1 above pellets are mixed afterloading each group into doscators. The strength of the final product is150 mg of bupropion with 50 mg of active drug in the first group ofpellets and 100 mg of active drug in the second group. The pellets arethen encapsulated into size “1” buff opaque/light blue opaque capsules.The total weight of the formulation (capsule+pellets) is 352 mg.

The resulting bupropion capsules were then tested according to the USPXXIII dissolution test (type 2, basket), at 50 rpm, at 37° C., in pH 7.5buffer and found to have the following release profile: Time (hours) %Released 1 28 2 40 3 50 4 58 6 70 8 80 10 83 12 87 14 88 16 90 18 90 2092

The release profile of the controlled release product of Example 3 isshown in FIG. 1 by the line with the filled in squares.

The resulting bupropion capsules were then tested according to USP XXIIIdissolution test (Type 2, basket), at 50 rpm, at 37° C., in SGF (pH 1.5)and found to have the following release profile: Time (hours) % Released1 0 2 2 3 4 4 6 6 12 8 21 10 40 12 57 13 64 16 68 17 71 20 74The release profile of the controlled release product shown in Example 3is shown in FIG. 2 by the line with the filled in squares.

The bupropion capsules of Example 3 were then analyzed in a sevenpatient test using techniques known in the art. Bupropion was firstdetected in the plasma about 1.4 hours after administration and showed asustained release over 24 hours.

The testing procedure is as described in Example 1. The results providedare given in table 4 and FIG. 4 and show that the mean plasma-timeprofile of the bupropion formulation differs from that of Zyban®.Bupropion had a delayed absorption; the relative bioavailability ofbupropion to Zyban® was 48% and 59% in terms of C_(max) and AUC values,respectively. The terminal elimination half-lives were similar. TABLE 4Parameter Example 3 Zyban ® G-Mean Ratio C_(max) (ng/ml) 56.9 114.8 0.48AUC_(0-inf) (ng · hr/ml) 531.7 889.5 0.59 T_(lag) (hr) 1.4 0.1 T_(max)(hr) 5.1 4.1 T_(1/2) (hr) 12.6 14.1

Thus, again, the C_(max) of the Example 3 product was reducedsignificantly more than the AUC compared to the reference product,demonstrating that an effective once-a-day product has been provided.

EXAMPLE 4

The pellets from Example 3 are taken as the second and third components.These pellets are loaded into the dosator along with active pellets andare filled into capsules in a ratio of 10:30:60 while maintaining thedosage at 150 mg bupropion. The blood profiles from this example willshow a C_(max) the same as in Table 3, but will show a slightlyincreased AUC, thereby rendering the G-mean ratio at about 1.00. Theamount of active pellets may be adjusted as is known in the art withoutundue experimentation based on the teachings of the present disclosurein order to substantially provide a G-Mean for AUC of approximately1.00.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, this specification is intended to coverall embodiments of the invention and modifications thereof that do notdepart from the spirit and scope of the invention.

All of the above-identified patents are hereby incorporated byreference.

1. A pelletized composition comprising: a core which comprises (a) aninert carrier, having (b) at least one aminoketone antidepressantlayered thereon.
 2. The composition of claim 1 wherein said core furthercomprises at least one binder.
 3. The composition of claim 2 whereinsaid binder comprises hydroxypropyl methylcellulose.
 4. The compositionof claim 1 further comprising at least one polymer for controlledrelease delivery of said aminoketone antidepressant.
 5. The compositionof claim 4 wherein said polymer is selected from the group consisting ofshellac, methacrylic acid copolymers, hydroxypropyl cellulose,hydroxypropyl methylcellulose, ethyl cellulose, cellulose aceate,cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate trimellitate, polyvinyl acetate phthalateand mixtures thereof.
 6. The composition of claim 4 wherein said polymeris water insoluble.
 7. The composition of claim 6 wherein said waterinsoluble polymer comprises a methacrylic acid copolymer.
 8. Thecomposition of claim 6 wherein said water insoluble polymer comprisesethylcellulose.
 9. The composition of claim 4 wherein said polymer isinsoluble below about pH
 7. 10. The composition of claim 4 wherein saidcomposition has a coating comprising a polymer.
 11. A pelletized dosageform comprising at least one composition of claim
 1. 12. The dosage formof claim 11 wherein said composition further comprises at least onebinder.
 13. The dosage form of claim 12 wherein said binder ishydroxypropyl methylcellulose.
 14. The dosage form of claim 11 furthercomprising at least one polymer for controlled release delivery.
 15. Thedosage form of claim 14 wherein said polymer is selected from the groupconsisting of shellac, methacrylic acid copolymers, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylcellulose, celluloseacetate, cellulose acetate butyrate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, cellulose acetate trimellitate, polyvinyl acetatephthalate and mixtures thereof.
 16. The dosage form of claim 15 whereinsaid polymer is water insoluble.
 17. The dosage form of claim 16 whereinsaid water insoluble polymer comprises ethylcellulose.
 18. The dosageform of claim 14 wherein said polymer is insoluble below about pH
 7. 19.The dosage form of claim 14 wherein said dosage form is for once dailyadministration.
 20. The dosage form of claim 11 wherein said dosage formis a tablet, caplet, capsule or palletized tablet.
 21. The dosage formof claim 11 comprising at least two distinct compositions of claim 1.22. The dosage form of claim 21 wherein at least one distinctcomposition is for controlled release.
 23. (canceled)
 24. (canceled) 25.(canceled)
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 29. (canceled)30. (canceled)
 31. A dosage form of claim 11, said dosage formcomprising a first pellet having a coating comprising methacrylic acidcopolymer and a second pellet having a coating comprising methacrylicacid copolymer.
 32. The dosage form of claim 31 wherein said methacrylicacid copolymer of said first pellet is pH independent.
 33. The dosageform of claim 31 wherein said methacrylic acid copolymer of said secondpellet is pH independent.
 34. (canceled)
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 36. (canceled)37. (canceled)